Blood Disorders
Hematopoiesis (hema=blood) refers to the process of formation, development and differentiation of all types of blood cells. All cellular blood components are derived from hematopoietic stem cells, including leukocytes and erythrocytes. The leukocytes or white blood cells (WBCs) contains the cells of the immune system defending the body against infectious disease and foreign materials. The erythrocytes are the non-nucleated, biconcave, disk-like cells which contain hemoglobin and these cells are essential for the transport of oxygen. A reduction in the number of white blood cells is called leukopenia whereas anemia refers to that condition which exists when there is a reduction below normal in the number of erythrocytes, the quantity of hemoglobin, or the volume of packed red blood cells in the blood. Disorders of the blood and the several kinds of leukopenia and anemia may be produced by a variety of underlying causes, including chemotherapy (e.g., chemotherapy induced anemia) and cancers (e.g., cancer related anemia). Therefore, there is a need for novel compositions and methods to stimulate hematopoiesis and to address the undesirable side effects of myelosuppression induced by chemotherapy and radiation therapy.
Inflammation
Immune Mediated Inflammatory Disease (IMID) refers to any of a group of conditions or diseases that lack a definitive etiology but which are characterized by common inflammatory pathways leading to inflammation, and which may result from, or be triggered by, a dysregulation of the normal immune response. Autoimmune disease refers to any of a group of diseases or disorders in which tissue injury is associated with a humoral and/or cell-mediated immune response to body constituents or, in a broader sense, an immune response to self. Current treatments for autoimmune disease can be broadly classified into two groups: those drugs which dampen or suppress the immune response to self and those drugs which address the symptoms that arise from chronic inflammation. In greater detail, conventional treatments for autoimmune diseases (e.g., primarily arthritis) are (1) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac, and ketoprofen; (2) Corticosteroids such as prednisone and dexamethasone; (3) Disease-Modifying Anti-Rheumatic Drugs (DMARDs) such as methotrexate, azathioprine, cyclophosphamide, cyclosporin A, Sandimmune™ Neoral™, and FK506 (tacrolimus); (4) Biologicals such as the recombinant proteins Remicade™ Enbrel™ and Humira™. While numerous therapies are available, conventional treatments are not routinely efficacious. More problematic is the accompanying toxicity which often prohibits the long-term use necessary with a chronic disease. Therefore, there is a need for compounds that are useful for the treatment of inflammation-related diseases, including chronic and non-chronic autoimmune disease.
Fibrosis and Kidney Disease
Fibrosis refers to the formation or development of excess fibrous connective tissue in an organ or tissue that can occur as a part of the wound-healing process in damaged tissue. It may be viewed as an exaggerated form of wound healing that does not resolve itself.
Fibrosis can occur on the skin but it can also occur in internal organs such as the kidney, heart, lung, liver and brain. In the case of organs, fibrosis will often precede sclerosis and subsequent shutdown of the affected organ. Of course, the most common consequence of complete organ failure is death. Thus, for example, pulmonary fibrosis is a major cause of morbidity and mortality. It is associated with the use of high dose chemotherapy (e.g., bleomycin) and bone marrow transplantation. Idiopathic pulmonary fibrosis (IPF) is a lung fibrotic disease for which the median survival is four to five years after the onset of symptoms. Currently there are no effective antifibrotic drugs approved for human needs. Therefore, the need exists for compounds that are useful for the treatment of fibrotic diseases.
Renal fibrosis is the common pathway underlying the progression of chronic renal injury to end-stage renal disease. The kidney is a structurally complex organ that performs a number of important functions: excretion of the waste products of metabolism, regulation of body water and salt, maintenance of acid balance, and excretion of a variety of hormones and autocoids. Diseases of the kidney are complex but their study is facilitated by dividing them by their effects on four basic morphologic components: glomeruli, tubules, interstitium, and blood vessels. Unfortunately, some disorders affect more than one structure and the anatomic interdependence of structures in the kidney implies that damage to one almost always secondarily affects the others. Thus, whatever the origin, there is a tendency for all forms of renal disease ultimately to destroy all four components of the kidney, culminating in chronic renal failure. For instance, in autoimmune diseases such as diabetes mellitus, the kidneys are prime targets to suffer tissue damage or lesions. Nephrectomy, or kidney removal, a procedure which is sometimes performed on patients with kidney cancer (e.g., renal cell carcinoma), may negatively impact kidney function in the remaining kidney. Chemotherapy and immunosuppressive therapy are also a source of harmful effects to the kidneys. Therefore, there exists a need for drugs with a good safety profile which can be administered to patients with kidney disease. There is also a need for pharmaceutical compounds which can prolong kidney health or protect it from deterioration to the point at which the kidney can no longer function.
The present invention addresses these needs for new treatment methods, compounds and pharmaceutical compositions. The invention provides new chemical entities and new treatment methods for preventing and/or treating (i) blood disorders, (ii) inflammation-related diseases and/or (iii) renal disorders and/or renal disorder complications along with any other organ dysfunction or lesion(s) arising from fibrotic disease.
Additional features of the invention will be apparent from a review of the disclosure, figures and description of the invention herein.